DE2711955A1 - PROCESS FOR THE PREPARATION OF 7-ALKOXY-3-BROMOMETHYLCEPHEMAS - Google Patents

Description

PFENNING - MAAS 40

X-4395

Eli Lilly and Company, Indianapolis, Indiana / V. St. A.

Process for the preparation of 7-alkoxy-3-bronunethylcephemes

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7-alkoxy-3-bromomethyl-3-cepheme v / earth by a new process produced in a reaction of a 3-methylenceepham with an alkali salt of a lower primary alcohol in the presence of a positive brominating agent at temperatures from -80 C to 0 C. The 3-bromomethylcephems obtained by the present process are valuable intermediate products for the production of known cephalosporin antibiotics.

3-halomethylcephenes are in the field of cephalosporins known and have proven to be valuable intermediates for those taking place via a nucleophilic exchange of the halogen atom Proven production of a number of well-known cephalosporin antibiotics. The 3-halomethyl cephems have so far been replaced by allylic Halogenation of the corresponding desacetoxycephalosporins (US Pat. Nos. 3,637,678 and 3,705,897) and by halogenation the corresponding deacetylcephalosporins (US Pat. No. 3,658,799). The production of 3-halomethylcephemes also by splitting 3-acetoxymethyl- and 3-carbamoyloxymethyl cephems with hydrogen halide acids.

GB-PS 1 407 348 describes the preparation of 3-halomethyl cephems described by first reacting a 3-methylenceepham with a free halogen and doing so as an intermediate 3-Haloge.n-3-halomethylcepham obtained then reacts with a base. In J. Am. Chem. Soc. 95 2403-2404 (1973) describes the 7-methoxylation of 3-acetoxymethylcephemes described with lithium methoxide and tert-butyl hypochlorite.

The invention now relates to a process for the preparation of 7-alkoxy-3-bromomethylcephems of the formula I.

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(O) η

R O

1 ^τ

CC

COOR

from 3-methylenceephams of the formula II

(0) q

Il

ΐ Λ. «TI 1

"TI

\ A.

iOOR

q stands for 1 cder O,

R is a carboxylic acid protecting group,

R _{1 is} primary C ₁ -Cg-AlKyI or benzyl and

the noun

tuenten R_

and R. amido groups of the formula

are,

R ₃ CNH-

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in which the substitute R ₃

(a) hydrogen, C ₁ -C ₃ -AlKyI, halomethyl, 3- (2-chlorophenyl) -5-methylisoxazol ~ 4-yl or 4-protected-amino-4-protected-carboxybuty1,

(b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert. Is butoxy or 4-methoxybenzyloxy,

(c) the group -R "represents, in which R" represents 1,4-cyclohexadienyl, phenyl or phenyl substituted with 1 or 2 substituents, these substituents being halogen, protected hydroxy, nitro, cyano, trifluoromethyl, Cj-C ^ - Are alkyl and / or C ₁ -C ₇ -AIkOXy,

(d) an arylalkyl group of the formula

R "- (O) _1n -CH ₂ - IV

represents, wherein R "has the above meaning and m is 0 or 1,

(e) a substituted arylalkyl group of the formula

R ¹ ' ¹ CH-

W V

denotes in which R ¹ ″ has the same meaning as the substituent R ″ indicated above, is 2-thienyl, 3-thienyl, bromo-2-thienyl or bromo-3-thienyl and W denotes protected hydroxy or protected amino, or

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(f) a heteroarylmethyl group of the formula

R "" - CK ₂ - VI

where R ^M "is 2-thienyl, 3-thienyl, 2-furyl, bromo-2-thienyl, bromo-3-thienyl, bromo-2-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl or 4 -Isoxazolyl stands,

with the proviso that the R. substituent is not bromothienylacetamido or Brorafurylacetamido means

characterized in that a compound of the formula II given above, in which R, R. and q have the meanings given above, with 4 to 8 equivalents of an alkali metal salt of a primary C ₁ -C ₇ -AlkOhOIs of the formula R-OH, in which R _{1 has the} above meaning, as a base in the presence of 4 to 8 equivalents of a positive brominating agent from the group of bromine, 1, B-diazabicyclo ^ S ^ .Q / undec-S-ene hydrobromide perbromide, iodine monobromide or tert-butyl hypobromite in an inert organic solvent at temperatures from -80 to 0 ° C.

In the above definitions of the individual general formulas, the indication C.-C_-alkyl refers to methyl, ethyl, n-propyl or isopropyl. C ₁ -C ₇ -AlkOXy is understood to mean radicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclohexyloxy or benzyloxy. The indication of primary C.-Cg-alkyl refers to methyl, ethyl, n-propyl, η-butyl, isobutyl, n-pentyl or n-hexyl. Examples of alkali salts of primary C ₁ -C ₇ alkoxides are lithium methoxide, sodium ethoxide, potassium ethoxide, lithium butoxide, sodium benzyl oxide or sodium n-propoxide.

If the substituent R ″ in the definition given above stands for substituted phenyl, then it can be act the following radicals: mono- or disubstituted halogen

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phenyl, such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3, 4-dibromophenyl, 3-chloro-4-fluorophenyl or 2-fluorophenyl, protected hydroxyphenyl, such as 4-benzyloxyphsnyl / 3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 4- (4-nitrobenzyloxy) phenyl, 2-phenacyloxyphenyl, 4-benzhydryloxypheny1 or 4-trityloxypheny1, Nitrophenyl, such as 3-nitrophenyl or 4-nitrophenyl, cyanophenyl, V7ie 4-cyanophenyl, mono- or dialkyl-substituted phenyl, such as 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-ethylphenyl or 3-n-propylphenyl, or Mono- or dialkoxyphenyl, such as 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-athoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl or 3-ethoxy-4-methoxyphenyl. The substituent R ″ can also be disubstituted phenyl with various Substituents such as 3-methyl-4-methoxyphenyl, 3-chloro-4-benzyloxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-methoxyphenyl, 3-chloro-4-nitrophenyl or 2-methyl-4-chlorophenyl.

Protected amino refers to an amino group which is protected with conventional protective groups, such as tert-butyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl. Examples of other conventional and suitable protecting groups are described by JW Barton in "Protective Groups in Organic Chemistry," JFW McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 2.

The term protected hydroxy relates to easily cleavable groups formed with a hydroxyl group, such as Formyloxy, chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy, 4-nitrobenzyloxy, trimethylsilyloxy, phenacyloxy, tert-butoxy, methoxymethoxy or tetrahydropyranyloxy. Further examples of suitable hydroxy protecting groups are given by C. B. Reese in "Protective Groups in Organic Chemistry", supra, Chapter 3.

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When stating, protected carboxy becomes a carboxy group understood, which is protected by a conventional carboxylic acid protecting group, in this way the carboxylic acid functionality to block or protect while responding to other functional parts of the compound performs. Such protected carboxy groups can easily be formed hydrolytically or hydrogenolytically split off the corresponding carboxylic acid. Examples of suitable carboxylic acid ester protecting groups are methyl, tert-butyl, Benzyl, 4-methoxybenzyl, C ^ -Cg -alkanovloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryl), Phenacyl, 4-halophenacyl, 2,2,2-trichloroethyl, succinimidomethyl or tri (C -C, alkyl) silyl. Other known and suitable carboxylic acid protecting groups are described by E. Haslam in "Protective Groups in Organic Chemistry", supra, Chapter 5. The nature of such ester-forming groups is not critical, provided the particular ester formed thereby under the reaction conditions described below is stable. Preferred. Carboxylic acid ester protecting groups are tert-butyl, 4-itethoxybenzyl, benzhydryl, 4-nitrobenzyl or 2, 2, 2-trichloroethyl.

The above statements do not give an exclusive definition the hydroxy, amino and carboxy protective groups again. Such groups are intended to give the reactive functional Groups are protected during the manufacture of the desired products, and these protecting groups are intended to be after their purpose has been fulfilled, they can be removed again without affecting the rest of the molecule. It's a series such protective group ^ known, and other groups of this type can be used in the present process just as well use.

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The type of side chain groups R_ and R. is also in accordance with the invention Process, namely in the process of converting a 3-methylencepham into a 3-bromomethylcephem, not critical. It should be noted, however, that some side chain groups, especially thienyl or furyl radicals Groups, especially under the reaction conditions applied to the heteroaryl group in the present process can be easily halogenated. By special measures, for example by using halogen acceptors, preferably in conjunction with low reaction temperatures, the possibility of simultaneous side chain halogenation can be avoided however, keep it to a minimum during the conversion desired according to the invention, and this will be discussed later received. However, after the side chains of the according to the invention Process produced compounds and the compounds derived therefrom in a later operation frequently split off and the resulting core esters are then reacylated again, the usefulness becomes of the process according to the invention by a possible side chain halogenation in no way affected.

Individual examples of amido groups of the above formula III are formamido, acetamido, propionamido, butyramido, 2-pentenoylamino, Chloroacetamido, bromoacetamido or 5-tert-butoxycarbonylamino-5-tert-butoxycarbonylvaleramido.

Individual examples of amido groups of the formula III in which the substituent R _{3 is} R ¹¹ are benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 4-methylbenzamido, 3,4-dichlorobenzamido, 4-cyanobenzamido, 3-bromobenzamido or 3- Nitrobenzamido.

Individual examples of amido groups of the formula III, in which R _{3 is} a group of the formula IV and m is 0, are cyclohexa-1,4-die.nylacetamido, phenylacetamido, 4-chlorophenylacetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 3-methylphenylacetamido , 4-bromophenylacetamido, 4-ethoxyphenylacetamido, 4-nitrophenylacetamido or 3,4-dimethoxyphenylacetamido.

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- ■

Individual examples of amido groups of the formula III, in which R _{3 is} a radical of the formula IV and m is 1, are phenoxyacetamides, 4-cyanophenoxyacetamido, 4-chlorophsnoxyacetamido, 3,4-dichlorophenoxyacetamido, 2-chlorophenoxyacetamido, 4-methoxyphenoxyacetamido, 2-Xthoxyphenoxyacetamido , 3,4-dimethylphenoxyacetamido, 4-isopropylphenoxyacetamido, 3-cyanophenoxyacetamido or 3-nitrophenoxyacetamido.

Individual examples of amido groups of the formula III in which R _{3 is} a substituted arylalkyl radical of the formula V in which W is protected hydroxy are 2-formyloxy-2-phenylacetamido, 2-benzyloxy-2- (4-methoxyphenyl) acetamido, 2- (4-Nitrobenzyloxy) -2- (3-chlorophenyl) acetamido, 2-chloroacetoxy-2- (4-methoxyphenyl) acetamido, 2-benzyloxy-2-phenylacetamido, 2-trimethylsilyloxy-2- (4-chlorophenyl) - acetamido or 2-benzhydryloxy-2-phenylacetamido. Individual examples of such groups in which W is protected amino are 2- (4-nitrobenzyloxycarbonylamino) -2- (2-thienyl) acetamido, 2- (2,2,2-trichloroethoxycarbonylamino) -2-phenylacetamido, 2-chloroacetamido 2- (1, 4-cyclohexadien-1-yl) acetamido, 2- (4-methoxybenzyloxycarbonylamino) -2- (4-methoxyphenyl) acetamido, 2-benzhydryloxycarbonylamino-2- (3-thienyl) acetamido or 2- (4- NitrobenzyloxycarbonyDamino 2-phenylacetamido.

Individual examples of Arazo groups of the formula III in which R _{3 is} a heteroarylmethyl group of the formula VI are 2-thienylacetamido, 3-thienylacetamido, 2-furylacetamido and a 2-thiazolylacetamido group of the formula

Il

~ CH CNH-

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a 1-tetrazolylacetamido group of the formula

/ N

• CH CM!

a 5-tetrazolylacetamido group of the formula

I,

• CH CNH-

NH

or a 3- (2-chlorophenyl) -5-methylisoxazol-4-ylamido group of the formula

ö-

'' CH

> CNH-

Examples of preferred amido groups of the formula III are formamido, acetamido, 4-nitrobenzyloxycarbonylamino, phenoxyacetamido, Phenylacetamido or 2-thienylacetamido. Phenylacetamido and phenoxyacetamido are particularly preferred.

The method of the invention is generally concerned with the production of T-alkoxy-S-bromomethylcephemes

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-Vf-

Reaction of 3-exomethylencephamsn with an alkoxide base. in the presence of a positive eromant.

The nature of the 7-alkoxy substituent on the resulting Cephemes are determined by the particular primary alkoxide base used in each case. Using from Lithiumüthoxid one obtains for example one 7-ethoxy-3-halomethylcephem.

The 3-exomethylene encephams of the formula II used as starting materials in the process according to the invention are described for the first time as a general class in US Pat. No. 3,275,626. 7-Amino- and 7-acylamino-3-exomethylencephams can be prepared by subjecting the corresponding cephalosporins, which have a 3-substituted methyl group, such as acyl oxymethyl, acylthiomethyl or quaternary ammonium methyl, to electroreduction (pH = 2-7) ( U.S. Patent 3,792,995). Optionally, the exomethylene encephams required as starting materials for the present process can also be prepared by the process described in Journal of Organic Chemistry 33, 2994 (1973). According to this, cephalosporanic acids are first treated with certain sulfur nucleophiles, such as thiourea, thiobenzoic acid, potassium ethylxanthate or sodium thiosulfate, and the products obtained, namely the C ₃ - (substituted) thiomethylcephem derivatives, are then reduced either with Raney nickel in aqueous sthanol acid or zinc in dimethylformic acid . Cephalosporanic acid derivatives have also already been converted into 3-exomethylencephams by treatment with chromium (II) salts in aqueous media. The 3-exomethylene cepham sulfoxides required as starting materials for the process according to the invention can be prepared by the. corresponding sulfides are oxidized with an equivalent amount of m-chloroperbenzoic acid.

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'M-

The way in which the reactants are combined is not critical in the process according to the invention, but care should be taken that the base does not come into contact with the exomethylencepham used as starting material without the halogenating agent also being present. In the absence of halogenating agents, the bases used in the process according to the invention react with the exomethylencepham at different rates, depending on the reaction temperature, with the formation of deacetoxymethylcephalosporins. Conversions of this type are known in the chemical literature, and reference is made, for example, to the Journal of Organic Chemistry 33, 2994 (1973). If the base and the exomethylencepham are added together, the brominating agent should preferably also already be present in the mixture or be added immediately afterwards. The conversion of the 3-exomethylencephams into 3-halomethylcephems is best carried out by converting a solution of the 3-exomethylencepham used as the starting material into a solution of an alkali salt of a primary C ₁ -C ₇ -AlkOhOIs and the positive brominating agent in an inert organic solvents.

As a medium for the halogenation process according to the invention any inert organic solvent can be used. Under an inert organic solvent is thereby understood an organic solvent, which under the conditions of the process neither with the reactants nor the Products reacts noticeably. A dry aprotic organic solvent is preferred. traces water, as it is present in commercially available dried solvents, is permissible. In general you should however, carry out the process according to the invention under anhydrous conditions. Examples of suitable solvents are aromatic hydrocarbons such as benzene, chlorobenzene, toluene, ethylbenzene or xylene, halogenated

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aliphatic hydrocarbons such as chloroform, riethylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene chloride), 1,1,2-trichloroethane or 1,1-dibromo-2-chloroethane, aliphatic nitriles such as acetonitrile or propionitrile, esters such as ethyl acetate or Butyl acetate, ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether or dimethoxyethane, or amides such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide (HMPA). Preferred solvents or Lösungsmittelgemisehe are those particularly preferred with freezing points below -10 ⁰ C. For the invention process solvents are methylene chloride, chloroform, 1,2-dichloroethane and tetrahydrofuran. Tetrahydrofuran is mainly used.

Bases with which the conversion according to the invention can be carried out are alkali metal salts of primary C ₁ -C ₇ -AlkOhOIe. Alkali salts of primary C ₁ -C ₇ alkoxides are understood to mean sodium, potassium and lithium salts of primary C ₁ -C ₇ alkoxides, such as methanol, ethanol, n-propanol, benzyl alcohol or n-hexanol. Individual examples of such alkoxide bases suitable for the process according to the invention are lithium methoxide, sodium methoxide, potassium ethoxide, sodium benzyloxide, lithium ethoxide, sodium n-propoxide and similar sodium, lithium and potassium salts of primary C ₁ -C ₇ alkoxides. Bases of the above type preferred for the process according to the invention are the alkali metal salts of methanol or ethanol. More preferred are the lithium salts thereof, particularly lithium methoxide being used.

The Cj -alkoxylation-C-j'-bromination according to the invention can be achieved by reacting an exomethylencepham of the formula II with 4 to 8 equivalents of an alkali salt of a primary C ₁ -C ₇ -AlkOhOIs in the presence of 4 to 8 equivalents of a positive brominating agent . The product of this conversion according to the invention is a 7-alkoxy-3-bromomethylcephem of the formula I. The best yields with this

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Ίο-

special conversion results when 8 equivalents each of an alkoxide base and a brominating agent are used per equivalent of cepham starting product used in connection with a halogen acceptor, the type of which will be given later is described.

The inventive method is carried out at temperatures between -30 ⁰ C and 0 ⁰ C. It is preferable to work at temperatures between -80 and -20.degree. C. However, if the side chain of the cepham used as starting material is at risk of bromination, the process according to the invention is preferably carried out at a temperature of below -40.degree. Examples of such halogen-sensitive side chains on carbon atom 7 are 2-thienylacetamido, 3-thienylacetamido or 2-furylacetamido groups. In addition to carrying out the process according to the invention at a lower temperature, if the starting material has halogen-reactive substituents, the reaction mixture should expediently also be treated with a halogen acceptor before it is allowed to reach a temperature of above 0.degree. Such a halogen acceptor serves to destroy any excess of brominating agent at a low reaction temperature and, through its presence, prevents or lowers the risk of undesirable side reactions between any excess of brominating agent and the 7-alkoxy-3-bromomethylcephemes present in the starting materials and the 7-alkoxy-3-bromomethylcephemes obtained as the product halogen reactive side chains.

Halogen acceptors in the process according to the invention understood such reagents, which under the applied process conditions neither with the as starting materials cephams used nor the cephemes obtained as products react, but with the brominating agent can react, thereby ensuring that the office

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mating agent or, more precisely, any excess thereof, cannot react with the 3-bromomethylcsphemums obtained in the process according to the invention. Typical ones suitable for the process according to the invention. Halogen acceptors are halogen reducing agents, but other halogen scavengers can also be used with which the excess of halogenating agent reacts preferentially (as opposed to a further reaction with the 3-bromomethylcephemes formed). Suitable halogen acceptors are (C.-C _g alkyl) sulfides, tri (C | -CG-alkyl) phosphites, olefins, acetylenes, or similar organic halogen-reactive agent. Aqueous solutions of known reducing inorganic salts, such as bisulfite, metabisulfite, thiosulfate or dithionite salts, can also be used in a similar manner.

Individual examples of those which are suitable in the process according to the invention Halogen acceptors from the class of sulfides and phosphites are dimethyl sulfide, di-n-propyl sulfide, dicyclohexyl sulfide, Methyl ethyl sulfide, trimethyl phosphite, triethyl phosphite or Tri-n-butyl phosphite. To typical olefins and acetylenes, which can be used as halogen acceptors in the process according to the invention include diethyl acetylenedicarboxylate, Vinyl ether including methyl vinyl ether, ethyl vinyl ether and other alkyl vinyl ethers, as well as vinyl esters, such as Vinyl acetate. Examples of suitable reducing inorganic salts are sodium bisulfite, potassium bisulfite, sodium metabisulfite, Potassium thiosulfate or sodium dithionite.

The halogen acceptors are normally added to the reaction mixture after the bromination-alkoxylation reaction has ended, what can be determined, for example, by comparative thin-layer chromatography, and preferably before the reaction mixture is allowed to come to above OC. If aqueous solutions are used as halogen acceptors reducing inorganic salts described above, then the addition of the salts is normally the first stage in

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the processing of the reaction mixture. Is the. However, the reaction temperature is below -20 ° C., then the inorganic halogen acceptors indicated above can also be added to the reaction mixture before the halogenation reaction is started. For example, 4'-methoxybenzyl-7- (2-thienylacetamido) -V-methoxy-S-bromomethyl-S-cephem - ^ - carboxylate can be prepared by adding a solution of 1 equivalent of 4'-methoxybenzyl-7- (2 -thienylacetamido) -3-methylencephem-4-carboxylate in tetrahydrofuran to a solution of 8 equivalents lithium methoxide, 8 equivalents of bromine, and 8 equivalents of trimethylphosphite in tetrahydrofuran is at a temperature of -60 ⁰ C. The trimethyl phosphite does not react with the brominating agent at the lower reaction temperature, but if the reaction mixture is allowed to rise above the reaction temperature after the methoxylation-bromination is complete, the trimethyl phosphite reacts with the excess bromine present in the reaction mixture.

The main product obtained in the above example without using a halogen acceptor is 4'-methoxybenzyl-7- ^ 2- (5-bromothienyl-acetamido / ^ - methoxy ^ -bromomethyl-S-cephem-4-carboxylate. however, 3-bromomethylcephem products formed in such reactions can still be used to prepare other 3-bromomethylcephem compounds. For example, 4'-methoxybenzyl- / 2- (5-bromothienyl) acetamido / ^ - methoxy-S-bromomethyl 3-cephem-4-carboxylate split off the side chain under practically non-aqueous conditions (PCl ₅ , pyridine / methanol), whereby the corresponding core ester 4'-methoxybenzyl-7-amino-7-methoxy-3-bromomethyl-3-cephem- 4-carboxylate is obtained, which can then be reacylated if desired.Conversions of 3-methylencephams into 7-alkoxy-3-bromomethylcephems, the side chains of which additionally have halogen substituents, therefore also fall under the process according to the invention.

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The amount of halogen acceptor used is not critical, provided that it leads to inactivation of the in the reaction mixture Existing excess of brominating agent is sufficient. In general, with a 1 to 10-fold excess or worked more on halogen acceptor.

Higher yields of the desired 3-bromomethylcephemes are generally obtained when using such halogen acceptors. In the method according to the invention are therefore expediently even then used halogen acceptors if the exomethylencepham used as the starting material does not have a halogen reactive side chain. The general use of halogen acceptors in the present Method is therefore preferred.

The inventive method is also preferably carried out such that the reaction mixture is treated with an excess of a protic acid before it is allowed to warm to a temperature of above about 0 ⁰ C. This optional, but preferred, measure serves to exclude any undesirable side reactions between the V-alkoxy-S-bromomethylcephem desired as the product and the excess of base present in the reaction mixture. Both organic and inorganic protic acids are suitable for this purpose. Individual examples of such acids are formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or hydrochloric acid.

The reaction time is generally between 5 minutes and 1 hour, and it depends to some extent on the reactants used in each case, the solvents used in each case and the temperature at which the reaction is carried out will. Usually the implementation is finished after

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• «f.

the reactants at the preferred temperatures for 5 to 15 minutes have been in contact. The progress of the reaction can be easily monitored by viewing the reaction mixture examined for example by comparative thin layer chromatography, so as to terminate the bromination-alkoxylation reaction to investigate.

Individual examples of conversions that can be achieved by the process according to the invention are:

tert-Buty l ^ -phenylacetamido ^ -methylencepham ^ -carboxy lat in tert-butyl-T-phenylacetanido-T-ethoxy-S-bromomethyl-B-cephem-4-carboxylate using lithium ethoxide and tert-butyl hypobromite;

Benzyl 7- (4-nitrobenzyloxycarbonylamino) -3-methylenceepham-4-carboxylate in benzyl 7- (4-nitrobenzyloxycarbonylamino) -T-methoxy-S-bromomethyl-S-cephem ^ -carboxylate using lithium methoxide and tert-butyl hypobromite;

4 '-Nitrobenzyl-T-acetamido-S-methylenceepham ^ -carboxylate-1-oxide in 4'-nitrobenzyl-T-acetamido-T-n-propoxy-S-bromomethyl-3-cephem-4-carboxylate-1-oxide using bromine and sodium n-propoxide;

2 ', 2 ¹ ^ ¹ -Trichloräthy1-7- (2-pheny 1-2-benzyloxyacetamido) 3-methylenceepham-4-carboxylate in 2', 2 ', 2'-trichloroethyl-7- (2-phenyl-2- benzyloxyacetamido) ^ -methoxy ^ -bromomethyl-3-cephem-4-carb.oxylate using bromine and sodium methoxide;

Benzhydryl 7-formamido-3-methylenceepham-4-carboxylate in Benzhydryl 7-formamido-7-methoxy-3-bromomethyl-3-cephem-4-carbpxylate using 1,5-diazabicyclo / ^. 4-O / -undec-5-ene-hydrobromide-perbromide and lithium methoxide;

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2'-iodoethyl 7- (2-formyloxy-2-phenylacetamido) -3-methylenceephane-4-carboxylate in 2'-iodoethyl-7- (2-formyloxy-2-phenylacetamido) ^ - benzyloxy-S-bromomethyl ^ -cephem ^ - carboxylate using tert-butyl hypobromite and Lithium benzyl oxide;

4 '-Methoxybenzyl ^ -phe.noxyacetamido ^ -rnethylencepham ^ - carboxylate in 4'-methoxybenzyl - ^ - phenoxyacetamido ^ -methGxy-3-bromomethyl-3-cephem-4-carbxylate using lithium methoxide and bromine;

2 ¹ , 2 ', 2 ' -Trichloräthy1-7- / 2- (4-nitrobenzyloxycarbonylamino) -2-phenylacetanido / -3-methylene-thylenecspham-4-carboxylate in 2 ', 2', 2 '-Trichloräthy1-7- / 2- (4-nitrobenzyloxycarbonylamino) -2-phenylacetamido / -7-propoxy-3-bromomethyl-3-cephem-4-carboxylate using lithium propoxide and tert-butyl hypobromite;

4'-nitrobenzyl-7- (2-f urylacetamido) -S-methylenceepham ^ -carboxylate in 4 '-nitrobenzyl-7- (2-furylacetamido) ^ -methoxy-S-bromomethyl-3-cephem-4-carboxylate using bromine, lithium methoxide and trimethyl phosphite;

tert-Butyl * -7- (4-chlorophenylacetamido) -3-methylenceepham-4-carboxylate in tert-butyl 7- (4-chlorophenylacetamido) -7-ethoxy-3-bromomethyl-3-cephem-4-carboxylate using lithium ethoxide and bromine;

4'-methoxybenzyl ^ -chloroacetamido-S-methylenceepham ^ -carboxylate in 4'-methoxybenzyl-7-chloroacetamido-7-ethoxy-3-chloromethyl-3-cephem-4-carboxylate using lithium ethoxide and iodine monobromide.

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The products obtained by the process according to the invention can be isolated and purified in the usual way, such as by chromatographic separation, filtration, crystallization and recrystallization.

The 3-bromomethylcephems obtained by the present process of formula I are valuable intermediates for the production of antibiotics. The sulfoxides can be known in Manner, for example using phosphorus tribromide or phosphorus trichloride in dimethylformamide, whereby the corresponding 3-bromomethylcephems are obtained. The. 3-Bromomethylcephemester are then cleaved converted the ester function into effective antibiotics (US Pat. No. 3,658,799). Deesterification can, depending on the type of ester group, by any of several known methods, for example (1) by treating with a Acid, such as trifluoroacetic acid, formic acid or hydrogen chloride acid, (2) treatment with zinc and an acid such as formic acid, acetic acid or hydrochloric acid, or (3) hydrogenation in the presence of palladium, platinum, rhodium or a compound thereof in suspension or on a carrier such as barium sulfate, activated carbon or alumina.

The 7-alkoxy-3-bromomethylcephems of the formula I can optionally also be replaced by nucleophilic exchange of the bromine radical convert into other 3- (substituted) methyl cephems. Processes of this type are very diverse to the person skilled in the art effective 3-Heteroarylthiomethylcephe.me known. The after 7-alkoxy-3-bromomethylcephems obtained by the process according to the invention are also intermediate products for the production of known and on the market cephemantibiotics. For example, benzhydryl 7- (2-thienylacetamido) -7-methoxy-3-bromomethyl-3-cephem-4-carboxylate react with calcium carbamate and remove the ester group, whereby the well-known antibiotic cefoxitin receives.

709840/0790

The invention is further illustrated by the following examples. The nuclear magnetic resonance spectra were measured with a Varian Associates T-60 spectrometer using tetramethylsilane as a reference standard. The chemical shifts (delta values) are Expressed in parts per million (ppm), and the coupling constants (J) represent vibrations per second.

example 1

4'-Nitrobenzyl-V-phenoxyacetamido-T-methoxy-S-bromomethyl ^ -

cephem-4-carboxylate

A solution of 0.256 g of dry methanol in 15 ml of tetrahydrofuran is added at a temperature of -80 ° C. with 4.17 g of 1.85 η methyllithium in tetrahydrofuran. The mixture is stirred for 5 minutes, after which 0.4 ml of bromine is added. The resulting mixture is then mixed with a solution of 0.483 g of 4'-nitrobenzyl-7-phenoxyacetamido-3-methylenceepham-4-carboxylate in 4 ml of tetrahydrofuran. The reaction mixture is then allowed to ^{come to 0 °} C. and stirred for 15 minutes at this temperature, whereupon 3 ml of trimethyl phosphite are added. The reaction mixture is then evaporated in vacuo and the residue obtained is dissolved in methylene chloride. The solution thus obtained is then washed in sequence three times with saturated sodium chloride solution, once with saturated sodium thiosulfate solution, twice with sodium bicarbonate solution and once with saturated sodium chloride solution. The washed solution is then dried and evaporated in vacuo to give an impure product which is purified by preparative thin layer chromatography using a gradient of benzene and ethyl acetate to give 140 mg of the title compound.

709840/0790

NMR spectrum (CDCl ₃ ) Delta 3.53 (s, 5, C ₂ -H and C ₆
4.42 (bs, 2, C ₃ -CHBr), 4.62 (s, 2, side sink.tten CH ₃ ),
5.14 (s, 1, C _c -H), 5.42 (s, 2, ester CII_), 6.8-8.4 (ArH).

The structure of this product is confirmed by comparison with an authentic sample of 4'-nitrobenzyl-T-phenoxyacetamido-7-methoxy-3-bromomethyl-3-cephem-4-carboxylate obtained by 7-methoxylation of 4'-nitrobenzyl 7-phenoxyacet aniido-3-broinnethyl-3-cephem-4-carboxylate by reaction with lithium methoxide and tert-butyl hypochlorite in tetrahydrofuran produces at -80 ⁰ C.

Example 2

Benzhydryl-7- (2-thieny! Acetamido) ^ -methoxy ^ -bromomethyl ^ -

cephem-4-carboxylate

According to the method described in Example 1, benzhydryl 7- (2-thienylacetamido) -3-methylenceepham-4-carboxylate is added with 8 equivalents of lithium methoxide in tetrahydrofuran in the presence of 8 equivalents of bromine at a temperature of
-HO ⁰ C um, whereby the compound mentioned in the title is obtained.

NMR Spectrum (CDCl ₃ ) Delta 3.41 (bs, 2, C ₃ -H), 3.46 (s, 3, C ₇ -OCII ₃ ), 3.83 (s, 2, side chains CH ₂ ), 4.20, 4.34 (ABq, 2, C ₃ -CH ₃ Br), 5.06 (s, 1, Cg-H) and 6.8-7.6 (m, 14, ArH and benzhydryl CH) .

709840/0790

Claims (14)

Claims 1. Process for the preparation of 7-alkoxy-3-bromine-methyl ceohems of the formula I (OJq Il RQ, S "Π I COOR from 3-methylenceephams of the formula II (0) q "-! - ■■ * - ·, Λ COOR q is 1 or O, R is a carboxylic acid protecting group, R is primary C - C ^ alkyl or benzyl and the noun tuenten R- and R. amido groups of the formula are, ORIGINAL IN&QM ^ 0/0 7 9 0 in which the substituent R ₃ 2 / M "*) O (a) _{denotes hydrogen, C 1} -C ₃ -AlCyI, halomethyl, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl or 4-protected-ainino-4-protected-carboxybutyl, (b) benzyloxy, 4-mitrobenzyloxy, 2,2,2-trichloroethoxy, tert, Is butoxy or 4-'lethoxybenzyloxy, (c) the group -R "represents, in which R" represents 1,4-cyclohexadienyl, phenyl or phenyl substituted with 1 or 2 substituents, these substituents being halogen, protected hydroxy, nitro, cyano, trifluoromethyl, C.-C- .-Alkyl and / or C ₁ -C ₇ -AIkOXy are, (d) an arylalkyl group of the formula R "- (0) -CII- IV ΓΠ Δ represents, wherein R "has the above meaning and m is 0 or 1, (e) a substituted arylalkyl group. the formula R ¹ ' ¹ CH- W V means where R '' 'is the same. Has meaning like as stated above. Substituent R ″ represents 2-thienyl, 3-thienyl, bromo-2-thienyl or bromo-3-thienyl and Vi is protected hydroxy or protected amino, or (f) a hateroarylmethyl group of the formula R "" - CH, - VI where R "" is 2-thienyl, 3-thienyl, 2-furyl, Bromo-2-thienyl, bromo-3-thienyl, bromo-2-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl or 4-isoxazolyl stands, 709840/0790 - A3 - with the proviso that the R. substituent is not bromothienylacetamido or Bromfury! acetamido means characterized in that a compound of the formula II given above, v / orin R, R. and q have the meanings given above, with 4 to 8 equivalents of an alkali salt of a primary C ₁ -C ₇ alkoxy of the formula R ₁ OH, where R _{1 has the} above meaning, as a base in the presence of 4 to 8 equivalents of a positive brominating agent from the group consisting of bromine, 1,5-diazabicyclo / 5.4.O / undec-5-ene-hydrobromide-perbromide, iodine monobromide or tert. -Butyl hypobromite in an inert organic solvent at temperatures of -80 to -20 ⁰ C is implemented. 2. The method according to claim 1 for the preparation of a compound of formula I from a compound of formula II, wherein R is methyl, tert-butyl, benzyl, 4-methoxybenzyl, C ₂ -Cg -alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, Benzhydryl, phenacyl, 4-halophenacyl, 2,2,2-trichloroethyl, tri (CC ₃ -alkyl) silyl or succinimidomethyl and q, R ₁ , R_ and R _{4 have} the meanings given in claim 1, characterized in that one a compound of the formula II with 4 to 8 equivalents of an alkali salt of a primary C ₁ -C ₇ -AlkOhOIs of the formula R ₁ OH, in which R _{1 has the} above meaning, as a base in the presence of 4 to 8 equivalents of a positive brominating agent from the bromine group , 1,5-Diazabicyclo / ^ 5.4 .O / undec-5-ene-hydrobromid-perbromid, iodine monobromide or tert-butyl hypobromite in an inert organic solvent at temperatures from -80 to -20 ⁰ C. 70S840 / 0790 3. The method according to claim 1 to 2 for the preparation of a compound of formula I from a compound of formula II, wherein R, R., R ₉ and R. have the meanings given in claim 2 and q is 0, characterized in that a compound of formula II with 4 to 8 equivalents of an alkali salt of a primary C.-C., alcohol of the formula R-OH, in which R _{1 has the} above meaning, as a base in the presence of 4 to 8 equivalents of a positive brominating agent from the Group bromine, 1,5-diazabicyclo ^ 5.4.O / undec-5-enhydrobromide-perbromide, iodine monobromide or tert-butyl hypobromite in an inert organic solvent at temperatures from -80 to -20 ⁰ C. 4. The method according to claim 1 to 3, characterized in that the base is a lithium salt used. 5. The method according to claim 1 to 4, characterized in that the reaction mixture, before it is allowed to ^{warm to a temperature of above 0 0} C, treated with an excess of a protic acid. 6. The method according to claim 1 to 5, characterized in that the positive brominating agent Bromine used. 7. The method according to claim 1 to 6, characterized in that the reaction is also carried out in the presence of a di (C.-C _c -alkyl) sulfide, a tri (C ₁ -C, - 709840/0790 alkyl) phosphites, diethyl acetylenedicarboxylate, methyl vinyl rithers, ethyl vinyl ether, vinyl acetate or a bisulf it, metabisulfite, thiosulfate or dithionite salt performs as a halogen acceptor. 8. The method according to claim 7, characterized in that the halogen acceptor are added to the reaction mixture before the reaction mixture is allowed to come to above 0.degree. 9. The method according to claim 7 to 8, characterized in that one is used as the halogen acceptor a halogen reducing agent is used. 10. The method according to claim 7 to 9, characterized in that one is used as the halogen acceptor a water-soluble bisulfite, metabisulfite, thiosulfate or dithionite salt is used. 11. The method according to claim 7 to 9, characterized in that one is used as the halogen acceptor Dinethyl sulfide, di-n-propyl sulfide, dicyclohexyl sulfide, Methyl ethyl sulfide, trimethyl phosphite, triethyl phosphite or Tri-n-butyl phosphite is used. 12. The method according to claim 11 for the preparation of a compound of the formula I from a compound of the formula II, vrorin q, R and R _{1 have} the meanings given in claim 3 and R ₃ and R _{4 are} amido groups of the formula III mentioned 709840/0790 are, where R _{3 stands} for an arylalkyl group of the formula IV, characterized in that a compound of the formula II is added to a solution of 8 equivalents of bromine, 8 equivalents of lithium methoxide and 10 equivalents of trimethyl phosphite per equivalent of exomethylencepham in tetrahydrofuran at a temperature of -70 ° C and the reaction mixture thus obtained is then treated with an excess of a protic acid before it is allowed to come to a temperature of above 0.degree. 13. The method according to claim 1 to 4, 6 to 7, 9 or 11 for the production of 4 '-nitrobenzyl ^ -phenoxyacetamido -? - methoxy-3-bromomethyl-3-cephem-4-carboxylate, thereby characterized in that 4'-nitrobenzyl-7-phenoxyacetamide-3-me thy lencepham-4-carboxylate reacts with lithium methoxide and bromine in an organic solvent and that Trimethyl phosphite is added to the reaction mixture. 14. The method according to claim 1 to 4 or 6 for the preparation of benzhydryl 7- (2-thienylacetamido) -7-methoxy-3-bromomethyl-3-cephem-4-carboxylate, characterized in that benzhydryl 7- (2-thienylacetamido) -3-methylenceepham-4-carboxylate with lithium methoxide and bromine in an organic solvent. 709840/0790